1. Field of the Invention
The present invention is in the field of medical devices and the methods for use thereof. More particularly it relates to systems and methods for monitoring and controlling the glycemic state of a subject to avoid undesirable states such as those corresponding to hyperglycemia, hypoglycemia, and neuroglycopenia.
2. Description of the Related Art
Tight control of blood glucose levels currently offers the best chance of reducing the long-term complications of diabetes mellitus. However, attempts to maintain near-normal glycemia often increase the risk of hypoglycemia. Although patients may perform self-monitored blood glucose (SMBG) tests four or more times per day, many episodes of hypoglycemia go undetected due to the absence of overt symptoms or because they occur at night, when glucose testing is rare. As a result, hypoglycemia is responsible for dramatic economic costs and many avoidable deaths each year.
Implantable glucose sensors are inserted beneath the skin or inside a blood vessel. This technology has been in development for quite some time, but the first prior art device only became commercially available in the past few years. Such monitors, which rely on advances in chemical sensors and biocompatible materials, are a step toward the ultimate goal: a glucose sensor that can be connected directly with an insulin delivery system to provide an artificial pancreas, the organ that controls blood glucose levels in the body.
The aforesaid prior art device can only operate for up to three days, which is certainly not a permanent solution, but one that yields enough information to improve a person's treatment regimen. The device records glucose levels for a healthcare professional to view during the patient's next office visit. A user performs two to four finger-prick blood glucose measurements to calibrate the device, which then supplies readings at five-minute intervals. Clinical researchers report identifying low glucose levels at night and high glucose after a meal that were previously unobserved by periodic pinpricks.
The aforesaid prior art device is an example of an enzymatic electrochemical sensor. In brief, an enzyme, commonly referred to as glucose oxidase, is fixed to an electrode and catalyzes the conversion of glucose into gluconic acid and hydrogen peroxide. The hydrogen peroxide then reacts at the sensing electrode, which is typically biased at 0.6 V, resulting in a measurable electric current.
Generally, implantable sensors can be categorized by the site of implantation and the method of measuring glucose. Subcutaneous sensors are inserted beneath the skin through a needle and measure glucose in interstitial fluid, the liquid between the cells. Other sensors are surgically affixed to the inside of a large vein and measure glucose in blood. Most sensors, like the aforesaid prior art device, employ an enzymatic conversion step to turn glucose into a chemical signal that can be easily measured electrochemically or optically.
The main challenge in developing a glucose sensor for implantation beneath the skin or in a vein is to maintain the sensors performance when it is exposed to the inside of the body over long periods of time. Almost without exception, interactions with the body cause a decrease in sensor sensitivity. For example, the body's immune system inevitably launches an attack and tries to encapsulate the sensor in protein. The glucose-blocking barrier thus created blunts sensor sensitivity and lengthens response time.
In addition, the body's warm, electrolytic environment corrodes metal electrodes and can inactivate enzymes, which leads to loss of measurement sensitivity and stability. Movement by a person wearing the device can create artifacts and noise that decrease sensitivity and specificity to glucose signals and also produce mechanical stresses that affect stability.
Many other interactions with the body's environment must also be taken into consideration. For instance, substances such as vitamin C and acetaminophen may react at the electrode, creating spurious signals. Such chemicals can also destroy hydrogen peroxide before it can react at the electrode, thus providing spurious results. To minimize this effect, many implantable systems include membranes that keep these substances away from the sensor.
Another problem is that when glucose levels are high, oxygen may become the limiting reactant in the electrochemical sensing scheme that prior art devices utilize. The result is signal saturation and a limited system operating range. To combat this drawback, some investigators have introduced membranes that limit the amount of glucose that reaches the sensor, or they eliminate the need for oxygen by using sensing schemes that rely on alternative reactions.
Still another method for defending against attacks by the body is microdialysis. In this technique, dialysis tubing, constructed from a material that allows only small molecules to pass therethrough, is implanted under the skin. A special fluid is pumped through the tube into which glucose diffuses. The fluid is then collected and measured with an external sensor. This strategy prevents proteins from encasing the sensor.
The design of the aforesaid prior art device addresses some of the destructive interactions with the body. It is built on a flexible substrate in order to minimize the effects of motion and to fit more comfortably in the patient. The sensor is also coated with a biocompatible polyurethane to minimize the immune system's response.
Besides the subcutaneous types, some fully implantable glucose measurement systems are currently presently under development. These systems have the ambitious goal of providing continuous blood glucose measurements for several years and interfacing with an implantable insulin pump. The hoped for result is closed-loop control of glucose levels—in effect, an artificial pancreas.
Limitations of the prior art which are relevant to the present invention include the following:
(1) Existing glycemic control and delivery methods/systems do not mimic the anatomo-physiologic process of whole body glucose metabolism and regulation, including route and mode, rate and timing of insulin delivery and number and location of putative glucose biosensors. Existing methods/systems do not take into account the fact that there is no compartment in the body at which all glucose is at the same concentration, not even in circulating blood plasma glucose. Models of glucose metabolism, that include the effects of insulin based on assumptions of concentration homogeneity upon which existing systems/methods are based, cannot be entirely accurate.
(2) The prevailing concept, that only three key elements—(i) a safe and reliable insulin delivery device, (ii) an accurate glucose-sensing unit, and (iii) a control system that modulates insulin delivery according to blood glucose levels, variation, and trends—are required for the development of an artificial Beta-cell, is correct but overly simplistic, as it ignores several important facts:                (a) blood glucose alone does not suffice to determine a hypoglycemic (or hyperglycemic) threshold and/or state;        (b) plasma glucose concentration alone is not a satisfactory, fully reliable indicator of neuroglycopenia (neurologic dysfunction), which is the most serious potential complication of hypoglycemia;        (c) the decisions and procedures for glycemic control in commercially available systems are entirely in the hands of the diabetic person who may suffer from hypoglycemic unawareness, which makes them incapable of using the control method or system to correct this serious and potentially harmful situation.        
(3) Prior art does not adequately incorporate into glucose control models or strategies the relative or partial dependency of glucose concentration at time, t0, upon its concentration at a previous time, t1.
(4) Glucose regulation is not under the exclusive control of insulin and the glucoregulatory response becomes either blunted or absent in type I diabetics at some point during the course of the illness. Even a single bout of hypoglycemia can significantly lower the threshold level of glucose required to initiate hypoglycemic awareness and the counter-regulatory response, causing hypoglycemia to be more serious and more likely to recur. Existing systems/methods do not take this into account.
(5) Prior art does not provide means of automatically protecting the brain from the deleterious effects of hypoglycemia on selectively vulnerable neuronal populations.
(6) The benefits of continuous subcutaneous insulin infusion, as performed in prior art systems, are contingent upon the subject's motivation, capacity to be educated, and ability to comply with complex instructions and procedures. This limits its applicability and usefulness, underscoring the need for a fully automated system.
(7) Continuous subcutaneous insulin infusion lacks the necessary reactivity to properly control/adjust insulin dose and the rate of release.
(8) Subcutaneous insulin absorption is unpredictable.
(9) Current systems suffer from inability to continuously and rapidly regulate or tune insulin delivery according to fluctuations in blood glucose concentrations.
(10) Glucose sensor performance degrades over time. For example, the body's immune system tries to encapsulate the sensor in protein, resulting in reduced sensor sensitivity and lengthened response time.
(11) Many glucose monitors are based on indirect measurements (e.g., enzymatic reactions). Other substances (besides glucose) may cause spurious readings in glucose sensors (e.g., Vitamin C and acetaminophen, or substances that react with hydrogen peroxide). Also some of these reactions require oxygen that may not be present in sufficient quantities to accurately complete the necessary reaction.
(12) Sensing processes may result in unwanted byproducts.
(13) Certain types of metal electrodes corrode, reducing sensitivity and stability.
(14) Electrode readings may be subject to movement-induced artifacts and other associated measurement noise that adversely affects sensitivity and specificity. Moreover, certain system designs may be prone to failure due to mechanical stresses and sensor movement.
(15) Some prior art systems use an external sensor to analyze acquired fluid (e.g. using microdialysis) which are inconvenient and have associated stigma for the user.
(16) Sensors placed in the blood stream may be prone to undesirable clotting or blood flow perturbations.
(17) Single sensor systems are more prone to failure than multiple sensor systems and are unable to accurately quantify complex glucose-insulin kinetics.